Although we have gained understanding regarding spinal cord injury (SCI) and its underlying mechanisms, creating an effective therapy to minimize tissue damage and maximize functional recovery is still unrealized. The only available treatment, methylprednisolone (MP), has limited clinical efficacy. Thus, utmost emphasis should be on early pharmacological intervention to the secondary damage pathways involving free radical production, inflammation, ischemia, loss of blood supply, calcium (Ca2+) overload with downstream proteinase activation, and axonal damage. By investigating new treatments, novel therapies to block inflammation, reduce cell and axonal damage, and restore blood supply may be discovered. Oxidative damage, inflammation, and intracellular Ca2+ influx are implicit in the initiation of secondary injury pathways for cell death after SCI. By understanding SCI pathophysiology, rational therapies will be designed to pre- vent cell death, sparing greater portions of the spinal cord after injury. Since several pathways cause cell damage and tissue destruction, blocking only one may not be optimal. Therefore, combining several drugs will likely be more neuroprotective. Our goal is to protect CNS cells from secondary damage by combining agents that preserve tissue and promote functional recovery. We will use the anti-oxidant melatonin (MEL) with the anti-inflammatory MP and the novel calpain inhibitor SJA6017 (SJA). In addition, treatment with angiogenesis-promoting factors, e.g. vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGR. will promote increased blood supply to the injured cord and further aid in functional recovery after combination therapy. We hypothesize that MEL will prevent oxidative damage resulting from ischemia/reperfusion, lipid peroxidation, and monocyte phagocytosis;MP will prevent infiltration of inflammatory cells into the spinal cord;and SJA will prevent over-activation of calpain with the consequence of blocking downstream calpain-mediated apoptotic events. Including VEGF and bFGF in this combination will further promote recovery bv protecting cells from secondary damage. Three specific aims will test the hypothesis: (1) examine the effects of MEL, MP, and SJA on the extent of cell death, inflammatory cell infiltration, white matter damage, oxidative stress, and calpain expression and activity following SCI;(2) using the parameters outlined in Specific Aim 1, investigate the efficacy of a triple (combination) therapy employing the treatments studied in Specific Aim 1, examine the efficacy in acute (48 hours) cord and in the weeks (chronic) following SCI by assessing white matter preservation and functional recovery;(3) investigate the mechanisms involved in angiogenesis and examine the effect of VEGF on capillary growth and blood supply following SCI and assess if addition of VEGF to triple treatment will offer maximum functional recovery after SCI.